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United States Patent |
6,231,875
|
Sun
,   et al.
|
May 15, 2001
|
Acidified composition for topical treatment of nail and skin conditions
Abstract
This invention relates to a method for topical treatment of human nail and
skin diseases, including fungal infections, bacterial infections, and
psoriatic infections. In addition, this invention relates to a method of
treating the general condition of human nails including their strength,
rate of growth and appearance. More particularly, the invention relates to
an acidified composition and methods of using said composition. Still
further the invention relates to an acidified lacquer useful in treating
human nails and skin.
Inventors:
|
Sun; Ying (Somerville, NJ);
Liu; Jue-Chen (Neshanic, NJ);
Kimbleton; Elizabeth (Princeton, NJ);
Wang; Jonas C. T. (Robbinsville, NJ)
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Assignee:
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Johnson & Johnson Consumer Companies, Inc. (Skillman, NJ)
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Appl. No.:
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265284 |
Filed:
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March 9, 1999 |
Current U.S. Class: |
424/401; 424/61; 424/404 |
Intern'l Class: |
A61K 007/00; A61K 007/04; A01N 025/34 |
Field of Search: |
424/401,61,78.03,404
|
References Cited
U.S. Patent Documents
4956467 | Sep., 1990 | Hinman et al. | 548/112.
|
4957730 | Sep., 1990 | Bohn et al. | 424/61.
|
5122533 | Jun., 1992 | Bar-On et al. | 514/390.
|
5264206 | Nov., 1993 | Bohn et al. | 424/61.
|
5461068 | Oct., 1995 | Thaler et al. | 514/399.
|
5683713 | Nov., 1997 | Blank et al. | 424/449.
|
5696164 | Dec., 1997 | Sun et al. | 514/562.
|
5958458 | Sep., 1999 | Norling et al. | 424/490.
|
Foreign Patent Documents |
1 000 567 | Dec., 1953 | DE.
| |
0 440 298 A1 | Jan., 1991 | EP.
| |
0 499 882 A1 | Feb., 1992 | EP.
| |
2 689 008 | Mar., 1992 | FR.
| |
534 810 A1 | Aug., 1992 | FR.
| |
WO 88/06884 | Sep., 1988 | WO.
| |
WO 94/16991 | Aug., 1994 | WO.
| |
WO 96/19186 | Jun., 1996 | WO.
| |
WO 97/28790 | Aug., 1997 | WO.
| |
Other References
PCT International Search Report dated Jul. 6, 1999.
PCT Search Report dated Aug. 24, 2000.
PCT Search Report dated Sep. 24, 1999.
Walters, Kenneth A., "Penetration of Chemicals into, and through, the Nail
Plate", Pharmacy International, Apr. 1985, pp. 86-89.
Kobayasi et al., "Enhancing Effect of N-Acetyl-L-Cysteine or
2-Mercaptoethanol on the In Vitro Permeation of 5-Fluorouracil or
Tolnaftate Through the Human Nail Plate", Chem. Pharm. Bull, Nov. 1998,
pp. 1797-1802.
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Howard; S.
Parent Case Text
This application claims benefit of provisional application No. 60/080,116,
filed Mar. 31, 1998.
Claims
What is claimed is:
1. An acidified composition comprising at least one active agent, at least
one acidifier, and at least one volatile solvent, wherein said at least
one acidifier is HCl.
2. The composition of claim 1 wherein said at least one acidifier is 37%
HCl or 10% HCl.
3. The composition of claim 1 wherein said at least one volatile solvent is
selected from a member of the group consisting of ethyl alcohol, isopropyl
alcohol, ethyl acetate, butyl acetate, and acetone and mixtures thereof.
4. The composition of claim 1 wherein said at least one volatile solvent is
selected from the group consisting of ethyl alcohol, isopropyl alcohol, or
ethyl acetate and mixtures thereof.
5. The composition of claim 1 wherein said at least one active agent is
selected from the group consisting of miconazole, econazole, ketoconazole,
itraconazole, fluconazole, bifoconazole, terconazole, butoconazole,
tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole,
butenafine, undecylenic acid, haloprogin, tolnaftate, nystatin, ciclopirox
olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin,
corticosteroids, calcipotriene, anthraline, minoxidil, minoxidil sulfate,
retinoids, cysteine and acetyl cysteine, methionine, glutathione, biotin,
finasteride and ethocyn, tea tree oil, mupirocin, neomycin sulfate
bacitracin, polymyxin B, l-ofloxacin, chlortetracycline hydrochloride,
oxytetracycline hydrochloride, tetracycline hydrochoride, clindamycin
phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium
chloride, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary
ammonium compounds, triclocarbon, triclosan, and pharmaceutically
acceptable salts thereof.
6. An acidified lacquer composition comprising at least one active agent,
at least one acidifier, at least one volatile solvent, and at least one
polymeric film former, wherein said at least one acidifier is HCl.
7. The acidified lacquer composition of claim 6 wherein said at least one
polymeric film former is selected from the group consisting of acrylic
copolymers/acrylic polymers, polymers of methacrylic acid, esters of
polymers of methacrylic acid, cellulose polymers, nitrocellulose, methyl
cellulose, ethyl cellulose, cellulose acetates, cellulose triacetate,
cellulose acetate butyrate, nylon, polyvinyl acetate, polyvinyl acetate
phthalate, and formaldehyde resin.
8. An acidified lacquer composition comprising at least one active agent,
at least one acidifier, at least one volatile solvent, and at least one
polymeric film former wherein said at least one active agent is present at
a concentration from about 0.1% to about 5%;
said at least one acidifier is present at a concentration from about 0.1%
to about 5%;
said at least one volatile solvent is present at a concentration from about
70% to about 95%; and
said at least one polymeric film former is present at a concentration from
about 0.1% to about 15%, wherein said at least one polymeric film former
is selected from the group consisting of acrylic copolymers/acrylic
polymers, polymers of methacrylic acid, esters of polymers of methacrylic
acid, cellulose polymers nitrocellulose, methyl cellulose, ethyl
cellulose, cellulose acetates cellulose triacetate, cellulose acetate
butyrate, nylon, polyvinyl acetate, polyvinyl acetate phthalate, and
formaldehyde resin.
9. The acidified lacquer composition of claim 8 wherein said at least one
active agent is selected from the group consisting of miconazole,
econazole, ketoconazole, itraconazole, fluconazole, bifoconazole,
terconazole, butoconazole, tioconazole, oxiconazole, sulconazole,
saperconazole, clotrimazole, butenafine, undecylenic acid, haloprogin,
tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine,
naftifine, elubiol, griseofulvin, corticosteroids, calcipotriene,
anthraline, minoxidil, minoxidil sulfate, retinoids, cysteine, acetyl
cysteine, methionine, glutathione, biotin, finasteride and ethocyn, tea
tree oil, mupirocin, neomycin sulfate bacitracin, polymyxin B,
l-ofloxacin, chlortetracycline hydrochloride, oxytetracycline
hydrochloride, tetrachcycline hydrochoride, clindamycin phsphate,
gentamicin sulfate, benzalkonium chloride, benzethonium chloride,
hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium
compounds, triclocarbon, triclosan, and pharmaceutically acceptable salts
thereof.
10. An acidified lacquer composition comprising about 1% of 37% HCl, about
2% of miconazole nitrate, about 70% ethyl alcohol, about 22% ethyl
acetate, and about 3% of an acrylic polymer.
11. An acidified lacquer composition comprising about 1% of 37% HCl, about
2% of miconazole nitrate, about 40% ethyl alcohol, about 22% ethyl
acetate, and about 15% of an acrylic polymer.
12. An acidified lacquer composition comprising at least one active agent,
at least one acidifier, at least one volatile solvent, and at least one
polymeric film former, wherein said at least one active agent is about
0.5% to about 2% of an antifungal drug, said at least one acidifier is
about 0.1% to about 1% of 37% HCl, said at least one non-volatile solvent
is about 40% ethyl alcohol and about 42% to about 44% ethyl acetate, and
said at least one polymeric film former is about 15% of an acrylic
polymer.
13. The acidified lacquer composition of claim 6 wherein said at least one
active agent is about 0.5% to about 2% of an antifungal drug, said at
least one acidifier is about 0.1% to about 1% of 37% HCl, said at least
one non-volatile solvent is about 70% ethyl alcohol and about 23% to about
24% ethyl acetate, and said at least one polymeric film former is about 3%
of an acrylic polymer.
14. A method of treating disease infected human nails or skin by topically
applying 1) an acidified composition comprising at least one acidifier, at
least one volatile solvent, and at least one active agent; or 2) an
acidified lacquer composition comprising at least one acidifier, at least
one volatile solvent, at least one active agent, and at least one
polymeric film former.
15. The method of claim 14 wherein said at least one acidifier is about 1%
of 37% HCl; said at least one active agent is from about 0.5% to about 3%
and is selected from the group consisting of miconazole, itraconazole,
econazole, ketoconzaole, clotrimazole, butenifine, terbinafine, and
pharmaceutically acceptable salts thereof; said at least one volatile
solvent is from about 40 to about 70% ethyl alcohol and from about 23% to
about 24% ethyl acetate; and said polymeric film former is from about 3%
to about 15% of an acrylic polymer.
16. The method of claim 14 wherein said at least one acidifier is about 1%
of 37% HCl, at least one active agent is about from about 1% to 2%
miconazole nitrate, said at least one volatile solvent is from about 40 to
about 70% ethyl alcohol and from about 23% to about 24% ethyl acetate, and
said at least polymeric film former is from about 3% to about 15% of an
acrylic polymer.
17. The method of claim 14 wherein said at least one active agent is
minoxidil and further comprising at least one active agent selected from
the group consisting of miconazole, itraconazole, econazole, ketoconzaole,
clotrimazole, butenfine, terbinafine, and pharmaceutically acceptable
salts thereof; said at least one acidifier is 37% HCl or 10% HCl; said at
least one volatile solvent is selected from the group consisting of ethyl
alcohol, isopropyl alcohol, or ethyl acetate; and said at least one
polymeric film former is selected from the group consisting of acrylic
copolymers/acrylic polymers, polymers of methacrylic acid and the esters
of polymers of methacrylic acid.
18. The method of claim 14 wherein said composition or said lacquer are
applied as an aerosol.
19. A method of improving and promoting healthy human nails and skin by
topically applying 1) an acidified composition comprising at least one
acidifier, at least one volatile solvent, and at least one active agent;
or 2) an acidified lacquer composition comprising at least one acidifier,
at least one volatile solvent, at least one active agent, and at least one
polymeric film former.
20. A method of improving and promoting healthy human nails by topically
applying 1) an acidified composition comprising at least one acidifier, at
least one volatile solvent, and at least one active agent; or 2) an
acidified lacquer composition comprising at least one acidifier, at least
one volatile solvent, at least one active agent, and at least one
polymeric film former.
21. A method of improving and promoting healthy human skin by topically
applying 1) an acidified composition comprising at least one acidifier, at
least one volatile solvent, and at least one active agent; or 2) an
acidified lacquer composition comprising at least one acidifier, at least
one volatile solvent, at least one active agent, and at least one
polymeric film former.
22. The method of claim 19 wherein said at least one active agent is
minoxidil and further comprising at least one active agent selected from
the group consisting of miconazole, itraconazole, econazole, ketoconzaole,
clotrimazole, butenafine terbinafine and pharmaceutically acceptable salts
thereof; said at least one acidifier is 37% HCl or 10% HCl; said at least
one volatile solvent is selected from the group consisting of ethyl
alcohol, isopropyl alcohol, or ethyl acetate; and said at least one
polymeric film former is selected form the group consisting of acrylic
copolymers/acrylic polymers, polymers of methacrylic acid and the esters
of polymers of methacrylic acid.
23. The method of claim 19 wherein said at least one active agent is
selected from the group consisting of miconazole, itraconazole, econazole,
ketoconzaole, clotrimazole, butenafine, terbinafine and pharmaceutically
acceptable salts thereof; said at least one acidifier is 37% HCl or 10%
HCl; said at least one volatile solvent is selected from the group
consisting of ethyl alcohol, isopropyl alcohol, or ethyl acetate; and said
at least one polymeric film former is selected form the group consisting
of acrylic copolymers/acrylic polymers, polymers of methacrylic acid and
the esters of polymers of methacrylic acid.
24. The method of claim 19 wherein said composition or said lacquer are
applied as an aerosol.
25. The composition of claim 1, wherein said at least one active agent is
an antifungal drug.
26. The composition of claim 1, wherein said at least one active agent is
miconazole or a pharmaceutically acceptable salt thereof.
27. The composition of claim 4, wherein said at least one active agent is
present at a concentration from about 0.1% to about 5%; said at least one
acidifier is present at a concentration from about 0.1% to about 5%; and
said at least one volatile solvent is present at a concentration from
about 70% to about 95%.
28. The composition of claim 27 wherein said at least one active agent is
selected from the group consisting of miconazole, econazole, ketoconazole,
itraconazole, fluconazole, bifoconazole, terconazole, butoconazole,
tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole,
butenafine, undecylenic acid, haloprogin, tolnaftate, nystatin, ciclopirox
olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin,
corticosteroids, calcipotriene, anthraline, minoxidil, minoxidil sulfate,
retinoids, cysteine and acetyl cysteine, methionine, glutathione, biotin,
finasteride and ethocyn, tea tree oil, mupirocin, neomycin sulfate
bacitracin, polymyxin B, l-ofloxacin, chlortetracycline hydrochloride,
oxytetracycline hydrochloride, tetrachcycline hydrochloride, clindamycin
phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium
chloride, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary
ammonium compounds, triclocarbon, triclosan, and pharmaceutically
acceptable salts thereof.
29. The composition of claim 27 wherein said at least one active agent is
an antifungal drug.
30. The composition of claim 27, wherein said at least one active agent is
miconazole or a pharmaceutically acceptable salt thereof.
31. The acidified lacquer of claim 6 wherein said at least one active agent
is selected from the group consisting of miconazole, econazole,
ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole,
butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole,
clotrimazole, butenafine, undecylenic acid, haloprogin, tolnaftate,
nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol,
griseofulvin, corticosteroids, calcipotriene, anthraline, minoxidil,
minoxidil sulfate, retinoids, cysteine and acetyl cysteine, methionine,
glutathione, biotin, finasteride and ethocyn, tea tree oil, mupirocin,
neomycin sulfate bacitracin, polymyxin B, l-ofloxacin, chlortetracycline
hydrochloride, oxytetracycline hydrochloride, tetrachcycline
hydrochloride, clindamycin phosphate, gentamicin sulfate, benzalkonium
chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium
chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan,
and pharmaceutically acceptable salts thereof.
32. The acidified lacquer of claim 6 wherein said at least one active agent
is an antifungal drug.
33. The acidified lacquer of claim 6, wherein said at least one active
agent is miconazole or a pharmaceutically acceptable salt thereof.
34. The acidified lacquer of claim 6 wherein said at least one volatile
solvent is selected from a member of the group consisting of ethyl
alcohol, isopropyl alcohol, ethyl acetate, butyl acetate, and acetone, and
mixtures thereof.
35. The acidified lacquer of claim 6 wherein said at least one volatile
solvent is selected from the group consisting of ethyl alcohol, isopropyl
alcohol, or ethyl acetate, and mixtures thereof.
36. The acidified lacquer of claim 35 wherein said at least one polymeric
film former is selected from the group consisting of acrylic
copolymers/acrylic polymers, polymers of methacrylic acid, esters of
polymers of methacrylic acid, cellulose polymers, nitrocellulose, methyl
cellulose, ethyl cellulose, cellulose acetates cellulose triacetate,
cellulose acetate butyrate, nylon, polyvinyl acetate, polyvinyl acetate
phthalate, and formaldehyde resin.
37. The acidified lacquer of claim 36, wherein said at least one active
agent is present at a concentration from about 0.1% to about 5%; said at
least one acidifier is present at a concentration from about 0.1% to about
5%; said at least one volatile solvent is present at a concentration from
about 70% to about 95%; and said at least one polymeric film former is
present at a concentration from about 0.1% to about 15%.
38. The acidified lacquer of claim 37 wherein said at least one active
agent is selected from the group consisting of miconazole, econazole,
ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole,
butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole,
clotrimazole, butenafine, undecylenic acid, haloprogin, tolnaftate,
nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol,
griseofulvin, corticosteroids, calcipotriene, anthraline, minoxidil,
minoxidil sulfate, retinoids, cysteine and acetyl cysteine, methionine,
glutathione, biotin, finasteride and ethocyn, tea tree oil, mupirocin,
neomycin sulfate bacitracin, polymyxin B, l-ofloxacin, chlortetracycline
hydrochloride, oxytetracycline hydrochloride, tetrachcycline
hydrochloride, clindamycin phosphate, gentamicin sulfate, benzalkonium
chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium
chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan,
and pharmaceutically acceptable salts thereof.
39. The acidified lacquer of claim 37 wherein said at least one active
agent is an antifungal drug.
40. The acidified lacquer of claim 37 wherein said at least one active
agent is selected from the group consisting of miconazole or
pharmaceutically acceptable salts thereof.
41. The acidified lacquer of claim 8 wherein said at least one active agent
is an antifungal drug.
42. The acidified lacquer of claim 8, wherein said at least one active
agent is miconazole or a pharmaceutically acceptable salt thereof.
43. The acidified lacquer of claim 8 wherein said at least one volatile
solvent is selected from a member of the group consisting of ethyl
alcohol, isopropyl alcohol, ethyl acetate, butyl acetate, and acetone, and
mixtures thereof.
44. The acidified lacquer of claim 8 wherein said at least one volatile
solvent is selected from the group consisting of ethyl alcohol, isopropyl
alcohol, or ethyl acetate, and mixtures thereof.
45. The acidified lacquer of claim 8, wherein said at least one active
agent is present at a concentration from about 0.1% to about 5%; said at
least one acidifier is present at a concentration from about 0.1% to about
5%; said at least one volatile solvent is present at a concentration from
about 70% to about 95%; and said at least one polymeric film former is
present at a concentration from about 0.1% to about 15%.
46. The acidified lacquer of claim 45, wherein said at least one active
agent is selected from the group consisting of miconazole, econazole,
ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole,
butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole,
clotrimazole, butenafine, undecylenic acid, haloprogin, tolnaftate,
nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol,
griseofulvin, corticosteroids, calcipotriene, anthraline, minoxidil,
minoxidil sulfate, retinoids, cysteine and acetyl cysteine, methionine,
glutathione, biotin, finasteride and ethocyn, tea tree oil, mupirocin,
neomycin sulfate bacitracin, polymyxin B, l-ofloxacin, chlortetracycline
hydrochloride, oxytetracycline hydrochloride, tetrachcycline
hydrochloride, clindamycin phosphate, gentamicin sulfate, benzalkonium
chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium
chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan,
and pharmaceutically acceptable salts thereof.
47. The acidified lacquer of claim 45 wherein said at least one active
agent is an antifungal drug.
48. The acidified lacquer of claim 45 wherein said at least one active
agent is selected from the group consisting of miconazole or
pharmaceutically acceptable salts thereof.
Description
FIELD OF THE INVENTION
This invention relates to a method for topical treatment of human nail and
skin diseases, including fungal infections, bacterial infections, and
psoriatic infections. In addition, this invention relates to a method of
treating the general condition of human nails including their strength,
rate of growth and appearance. More particularly, the invention relates to
an acidified composition and methods of using said composition. Still
further the invention relates to an acidified lacquer useful in treating
human nails and skin.
BACKGROUND OF THE INVENTION
Onychomycosis is a fungal disease of the human nail. The symptoms of this
disease are a split, thickened, hardened, and rough nail plates. This is
caused by any of a number of organisms and is particularly prevalent in
the elderly. Typically fungal infections are treated by topical
application of antifungal agents and/or oral administration of antifunal
agents. Unlike other fungal infections, there is no topical treatment for
onchomycosis which is approved by the United States Food and Drug
Administration. It is desirable to treat this disease topically due to the
potential for side effects which have been associated with some of the
oral treatment regimens. One reason for the absence of a topical treatment
is that in this disease, the symptomatic thickened nail plate prevents
topical agents from reaching the site of the infection. The target sites
for the treatment of onychomycosis reside in the nail plate, nail bed and
nail matrix, as set forth in FIG. 1. It has been shown that if the nail
barrier is modified, reduced, or eliminated, topical antifungal drug
treatment is effective for onychomycosis. For example, both miconazole and
ketoconazole have been demonstrated to be effective in topically treating
onychomycosis after nail removal. Nevertheless, most consumers would
certainly prefer a less dramatic treatment of nail fungal infection than
removal of the nail.
The nail plate is thick, hard, dense, and represents a formidable barrier
for drugs to be able to penetrate in a therapeutically required quantity.
Although nail material is similar to the stratum corneum of the skin,
being derived from epidermis, it is composed primarily of hard keratin,
which is highly disulfide-linked, and is approximately 100-fold thicker
than stratum corneum. In order to deliver a sufficient amount of drug into
the nail plate, the permeability of the nail plate to the drug must be
enhanced. This is particularly true in fungal diseases where a common
symptom of the disease is thickened nail plate. In an onychomycosis study,
patients' small toe nails were 5 mm and their large toe nails were 9 mm.
When compared to non-infected nail dimensions of 0.5 mm for small toe
nails and 1.5 mm for big toe nails, the infected nail presents a
formidable barrier to topical treatment.
Nail plates have a high sulphur content in the form of disulfide bonds.
U.S. Pat. No. 5,696,164 (Sun et al., 1997) discloses the use of
thio-containing amino acids and its derivatives (i.e.,
sulfhydryl-containing amino acids), such as cysteine and N-acetyl
cysteine, and urea to increase drug permeability in a nail plate, by
breaking disulfide bonds in nail keratin to increase drug penetration into
and through the nail. It was shown that a significant enhancement in
topical drug delivery through nail was achieved. European Patent
Application EP 503988 A1 (1992) discloses a composition to treat
onychomycosis, comprising nail-penetration agents, such as glycols, glycol
ethers, dimethyl sulfoxide, caprolactam, and other hydrophilic compounds
to facilitate the penetration of allylamine fungicides into the nail.
Nail lacquer, also known as nail coating, polish, enamel and/or varnish, is
a popular form of nail care products. A drug-containing nail lacquer is
the most convenient and most acceptable nail treatment method to treat
nail diseases such as onychomycosis and psoriasis-affected nail. As
described above, it is essential to have a drug-containing nail lacquer
that is capable of delivering a drug or drugs into and through the nail in
therapeutically sufficient quantity. In addition, the drug-containing
lacquer should not be irritating to the skin tissue adjacent to the nail.
The drug in the lacquer formulations should be stable enough to meet the
normally required 2-year shelf life for a pharmaceutical product.
Nail lacquers containing therapeutic agents have been known in the past.
For example, U.S. Pat. No. 4,957,730 (1990) describes a nail varnish
containing a water-insoluble film-forming substance and antimycotic
compound. U.S. Pat. No. 5,120,530 (1992) describes a antimycotic nail
varnish containing amorolfine in quaternary ammonium acrylic copolymer.
The water-insoluble film former is a copolymerizate of acrylic acid esters
and methacrylic acid esters having a low content of quaternary ammonium
groups. U.S. Pat. No. 5,264,206 (1993) describes a nail lacquer with
antimycotic activity, which contains an antimycotic agent and
water-insoluble film formers including polyvinyl acetate, a copolymer of
polyvinyl acetate and acrylic acid, copolymers of vinyl acetate and
crotonic acid, monoalkyl maleate, etc. U.S. Pat. No. 5,346,692 (1994)
describes a nail lacquer for treating onychomycosis, comprised of a
film-forming agent, an antimycotically active substance, and urea,
wherewith the antimycotic agent and urea are liberated from the lacquer
when the lacquer is applied. A preferred formulation comprises cellulose
derivatives as film former, clotrimazole as the antimycotic agent, dibutyl
phthalate as a plasticizer, and a mixture of acetone and ethanol as
solvent. U.S. Pat. No. 5,487,776 (1996) describes a nail lacquer
composition which forms a water permeable film containing griseofulvin
when the organic solvent system evaporates, wherein a portion of the
griseofulvin is in solution and a portion of griseofulvin is present as a
colloidal suspension. European Patent Application EP515312 A2 (1992)
describes a nail lacquer containing terbinafine or its hydrochloric acid
salt as an antimycotic agent, solvents, and a polymeric film former
consisting of di-butyl phthalate, Paraloid A-21 acrylic resin, poly(vinyl
acetate) etc. However, these patents and publication mention little, if
any, information concerning nail penetration enhancement of drugs in these
disclosures.
Notwithstanding these instances, however, simply placing a drug in a
conventional lacquer formulation without any means of enhancing nail
penetration through the nail is unlikely to achieve the desired
therapeutic goal. This is particularly true with certain classes of
antifungal medication, particularly, azoles and imidazoles. These drugs
are often quite insoluble and therefore it is difficult to prepare topical
formulations of these drugs. Furthermore, many topical imidazole
formulations have been known to be extremely irritating.
Furthermore, when treating onychomycosis, once the nail fungi are killed,
the replacement non-infected nails grow relatively slowly. Thus, it can
take from six months for non-infected finger nails, and 12 to 18 months
for non-infected toe nails to grow and replace discolored and/or deformed.
Preferably, a topical product for nail disease treatment, such as
onychomycosis, is not only efficacious in eliminating the fungi, but in
shortening the waiting period for the healthy nail to grow. U.S. Pat. No.
4,927,626 (1990) describes the topical application of minoxidil to
increase the growth of unguis in animals, including human nail. However,
it neither describes nor suggests how to deliver the minoxidil through the
nail.
The recurrence rate of onychomycosis is relatively high for the patients
who have been treated and considered "cured". Because certain people are
more prone to onychomycosis, prophylactic products, such as a
drug-containing lacquer, are desirable to prevent the relapse of
onychomycosis.
Aside from the antifungal diseases associated with nails, there are
antifungal diseases associated with human skin. One particular sight of
infection is the feet where diseases associated with ring worm, commonly
known as athlete's foot, are prevalent.
There are a number of commercial treatments for this disease containing
miconazole nitrate as the active ingredient. However, despite these
commercial products, a formulation which is capable of delivering a
greater percentage of the active ingredient than the commercial products
would be useful.
Therefore it is an object of the current invention to prepare a
drug-containing composition which is capable of delivering a drug or drugs
into and through human nails and skin in a therapeutically sufficient
quantity. In addition it is an object of this invention to prepare a
composition which adheres to the nail and skin for a prolonged period of
time. Further it is an object of the invention to prepare a composition
which is non-irritating to human skin. It is still further an object of
the invention to prepare a lacquer containing said composition. Further,
the composition containing lacquer should not be irritating to the skin
tissue adjacent to the nail. Further still, the composition and lacquer
should have the shelf required of a pharmaceutical product.
SUMMARY OF THE INVENTION
The present invention provides an acidified composition to treat nail and
skin diseases such as onychomycosis, psoriatic nails, psoriasis of the
skin, versicolor, ringworm, plantar tinea pedis, Jock itch, and athlete's
foot.
Particularly, the invention includes an acidified composition comprising at
least one active agent, at least one acidifier, and at least one volatile
solvent. Further, the invention includes a method of treating disease
infected human nails or skin by topically applying 1) an acidified
composition comprising at least one acidifier, at least one volatile
solvent, and at least one active agent; or 2) an acidified lacquer
composition comprising at least one acidifier, at least one volatile
solvent, at least one active agent, and at least one polymeric film
former. Still further, the invention includes a method of improving and
promoting healthy human nails and skin by topically applying 1) an
acidified composition comprising at least one acidifier, at least one
volatile solvent, and at least one active agent; or 2) an acidified
lacquer composition comprising at least one acidifier, at least one
volatile solvent, at least one active agent, and at least one polymeric
film former.
In addition, the invention contemplates an acidified lacquer composition
comprising at least one active agent, at least one acidifier, at least one
volatile solvent, and at least one polymeric film former.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a depiction of the target sites for the treatment of
onychomycosis.
FIG. 2 is a graph of the drug partitioning results for miconazole nitrate
lacquer formulations.
FIG. 3 is graph of the drug partitioning results for itraconazole lacquer
formulations.
FIG. 4 is a graph of the permeation profiles for miconazole nitrate.
FIG. 5 is a graph of the permeation of miconazole nitrate lacquers.
FIG. 6 is a graph which compares the amount of miconazole nitrate retained
on the skin using different miconazole nitrate formulations.
FIG. 7 shows the relative miconazole content in epidermis, dermis and
receptor media.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates an acidified composition comprising at least one
active agent, at least one acidifier, at least one volatile solvent, and
at least one active agent.
As used herein the term "acidifier" refers to substances which are liquids
having an apparent pH of .ltoreq.1, or solids having a pKa.ltoreq.5.
Apparent pH is the pH reading measured by a glass pH electrode. The
preferred acidifiers are 37% HCl, 10% HCl, sulfuric acid, o-phosphoric
acid, nitric acid, acetic acid, L (+)-lactic acid, salicylic acid, and
glycolic acid. The particularly preferred acidifiers are 37% HCl and 10%
HCl. If the total weight of the acidified composition is 100 parts, the
acidifier should be about 0.05 to about 50% w/w (w/w=weight/weight),
preferably, from about 0.1% to about 10%, more preferably form about 0.5%
to about 5%.
The term "volatile solvent" refers to liquid substances which evaporate
more rapidly than water. The volatile solvent need not be anhydrous but
should have less than 30%, preferably less than 10% with most preferably
less than 2% water. Examples of such solvents include but are not limited
to ethyl alcohol, isopropyl alcohol, ethyl acetate, butyl acetate,
acetone, and mixtures thereof. The preferred volatile solvents are ethyl
alcohol, isopropyl alcohol, ethyl acetate, and butyl acetate. If the total
weight of the acidified composition is 100 parts, preferably, the volatile
solvent is 90-98% w/w.
As used herein, the term "active agents" refers drugs for treating diseased
nails, nutrients or nail conditioners which may be used to improve damaged
nails or maintain healthy, and nail growth promoters which may be used on
damaged or healthy nails. All of the aforementioned types of active agents
may be used to treat the tissue surrounding the nail, and skin whether
that tissue is healthy or diseased. The active agents include but are not
limited to antifungal drugs used to treat onychomycosis and athlete's
foot, antibiotics (or antiseptics) for bacterial infection of nails,
tissue surrounding the nails and other human tissues, and antipsoriatic
drugs for psoriatic nail and skin treatment. Examples of antifungal drugs
include but are not limited to miconazole, econazole, ketoconazole,
itraconazole, fluconazole, bifoconazole, terconazole, butoconazole,
tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole,
undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox
olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, and
their pharmaceutically acceptable salts. The preferred antifungal drugs
are an azole, an allylamine, or a mixture thereof. Preferred azoles are
selected from the group consisting of itraconazole, ketoconazole,
miconazole, econazole, fluconazole, voriconazole, clotrimazole,
butenafine, undecylenic acid, clioqinol, and their pharmaceutically
acceptable salts. Preferred allylamines are selected from the group
consisting of terbinafine, naftifine and mixtures thereof.
Examples of antibiotics (or antiseptics) include but are not limited to
mupirocin, neomycin sulfate, bacitracin, polymyxin B, l-ofloxacin,
tetracyclines (chlortetracycline hydrochloride, oxytetracycline
hydrochloride and tetrachcycline hydrochoride), clindamycin phsphate,
gentamicin sulfate, benzalkonium chloride, benzethonium chloride,
hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium
compounds, triclocarbon, triclosan, tea tree oil, and their
pharmaceutically acceptable salts. Preferred antibiotics and antiseptics
include mupirocin, neomycin sulfate, bacitracin, polymyxin B, l-ofloxacin,
tetracyclines, benzalkonium chloride, benzethonium chloride, triclocarbon,
and triclosan.
Examples of antipsoriatic drugs include but are not limited to
corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate,
clobetasol propionate, diflorasone diacetate, halobetasol propionate,
amcinonide, desoximetasone, fluocinonide, fluocinolone acetonide,
halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone
verlerate, hydrocortisone butyrate, aclometasone dipropionte,
flurandrenolide, mometasone furoate, methylprednisolone acetate),
calcipotriene and anthraline. Preferred antipsoriatic drugs include
betamethasone dipropionate, betamethasone valerate, and clobetasol
propionate.
When the active agents are nail growth promoters, such agents include but
are not limited to minoxidil, minoxidil sulfate, retinoids, cysteine and
acetyl cysteine, methionine, glutathione, biotin, finasteride and ethocyn,
as well as pharmaceutically acceptable salts of these compounds. The
preferred growth promoter are minoxidil, minoxidil sulfate, retinoids,
cysteine and acetyl cysteine. The particularly preferred nail growth
promoters are 2% minoxidil, 2% minoxidil sulfate, and 0.1% retinol.
When the active agents include nutrients, they include but are not limited
to vitamins, amino acids, and their derivatives. Examples of such agent
include but are not limited to vitamin B complex: thiamine, nicotinic
acid, biotin, pantothenic acid, choline riboflavin, vitamin B.sub.6,
vitamin B.sub.12, pyridoxine, inositol, carnitine; ascorbic acid, ascorbyl
palmitate, vitamin A, vitamin K, vitamin E, vitamin D, cysteine and
N-acetyl cysteine, herbal extracts, and their derivatives.
When the active agents include nail conditioners they include but are not
limited to mineral-containing compounds, flavonoids and retinoids. These
nail conditioners improve general nail conditions, such as strengthening
the nails to prevent nail chipping and cracking, and to beautify the
nails. Examples of such agents include but are not limited to calcium
pantothenate, calcium carbonate, and calcium gluconate. Examples of
retinoids include but not limited to retinol (Vitamin A alcohol), retinal
(Vitamin A aldehyde), retinyl acetate, etinyl palmitate, retinoic cid,
9-cis-retinoic acid and 13-cis-retinoic acid. When retinoids are the
active agents, the concentration of retinoids is from about 0.01% to about
0.5%, preferably, from about 0.05 to about 0.1%. Examples of flavonoids
include but not limited to naringenin, quercetin, catechins (e.g.,
epigallocatechin gallate), theaflavins, robustaflavone, hinokiflavone,
amentoflavone, agathisflavone, volkensiflavone, morelloflavone,
rhusflavanone, and succedangeaflavanone.
Overall, the preferred active agents are miconazole nitrate, itraconazole,
econazole nitrate, ketoconzaole, clotrimazole, and terbinafine. If the
total weight of the acidified composition is 100 parts, the active agent
is present in about 0.05% to about 10% w/w, preferably, from about 0.1% to
about 5%, more preferably from about 0.5% to about 2%.
Aside from the acidifier, the volatile solvent, and the active agent, the
compositions of this invention may include other substances, such as
preservatives, cosmetic additives, antioxidants, chelating agents and
pigment flakes. Examples of such agents include but are not limited to
benzoic acid, benzyl alcohol (as preservative), glycerol, propylene glycol
as emollient, butylated hydroxyltoluene, butylated hydroxyanisole,
ascorbic acid, ascorbyl palmitate, N-acetyl cysteine as antioxidant,
citric acid, edetic acid and its sodium salts as chelating agent.
An example of a typical acidified composition comprises 1% clotrimazole as
active agent, 0.1% concentrated HCl (37% HCl by weight) as acidifier, and
98.7% ethyl alcohol as volatile solvent. An example of a topical
formulation containing this composition comprises 1% clotrimazole as
active agent, 0.1% concentrated HCl (37% HCl by weight) as acidifier, 0.1%
butylated hydroxyltoluene as antioxidant, 0.1% citric acid, and 98.7%
ethyl alcohol as volatile solvent.
The invention includes an acidified lacquer composition comprising at least
one active agent, at least one acidifier, at least one volatile solvent,
and at least one polymeric film former. The terms, active agent,
acidifier, and volatile solvent have their aforementioned meanings. The
acidifier should be present at about 0.05 to 10% w/w, preferably, from
about 0.1% to about 5%, more preferably form about 0.5% to about 2%. The
volatile solvent should be present preferably, at about 70 to about 98%
w/w. The active agent should be present at about 0.05% to 10% w/w,
preferably, from about 0.1% to about 5%, more preferably from about 0.5%
to about 2%.
As defined herein, the term "lacquer" refers to a liquid substance which
typically dries to form a continuous or a non-continuous film by
evaporation of the solvent.
As defined herein, the term "polymeric film former," is a polymer which may
be added to a volatile solvent and other substances to form a polymeric
solution which may be applied to the skin to form a film. Examples of
polymeric film formers include but are not limited to acrylic
copolymers/acrylic polymers, (such as Carboset.RTM. or Avalure.RTM.
polymers, made by BF Goodrich); polymers of methacrylic acid and its
esters (such as Eudragit.RTM. polymers: S, L, RS and RL series, made by
Rohm Pharma); cellulose polymers, nitrocellulose, methyl cellulose, ethyl
cellulose, cellulose acetates (such as cellulose triacetate, cellulose
acetate butyrate); nylon, polyvinyl acetate, polyvinyl acetate phthalate,
formaldehyde resin, and polymer blends of the aforementioned polymers.
Preferred polymeric film formers are selected from the group consisting of
acrylic copolymers/acrylic polymers, (such as Carboset.RTM. or
Avalure.RTM. polymers, made by BF Goodrich); polymers of methacrylic acid
and its esters, (such as Eudragit.RTM. polymers: S, L, RS and RL series,
made by Rohm Pharma).
Lacquers may have different viscosities. The viscosity of the lacquer is
related to the thickness of the film that will be left on a surface once
the volatile solvent has evaporated. If one desires a thick and viscous
lacquer, which will deposit a thick film on a surface, the concentration
of the polymeric film former should be about 0.1% to about 30%, preferably
from about 0.5% to about 15% of the total composition. If one desires a
thin lacquer which will deposit a thin film on a surface, the
concentration of the polymeric film former should be about 0.1% to about
15%, preferably about 0.5% to about 5.0% of the total composition.
The acidified lacquers of the invention may have other additives such as
plasticizers (to maintain the pliability of the film formers),
non-volatile drug solubilizers, cosmetic additives, and pharmaceutical
additives.
When plasticizers and non-volatile drug solubilizers are used, examples of
these substances include but are not limited to phthalate esters (e.g.,
dibutyl phthalate), citrate esters, triacetin, isopropyl myristate,
N-methyl-2-pyrrolidone, fatty acids and fatty acid esters, propylene
glycol, butylene glycol, hexylene glycol, propylene carbonate,
poly-propylene glycol, methoxypolyethylene glycol, polyethylene glycol,
glycerin. When plasticizers are used they are preferably about 0.001 to
about 10% by weight of the total composition.
Pharmaceutical additives include but are not limited to antioxidants and
chelating agents. Examples of antioxidants include but are not limited to
butylated hydroxyltoluene, butylated hydroxyanisole, ascorbic acid,
ascorbyl palmitate, N-acetyl cysteine. Examples of chelating agents
include but are not limited to citric acid, edetic acid and its sodium
salts. Cosmetic additives include, but are not limited to, coloring
agents, fragrance, pigments, as well as powders of silica, zinc oxide, and
titanium oxide.
A typical acidified lacquer composition comprises 1% clotrimazole as active
agent, 0.1% concentrated HCl (37% HCl by weight) as acidifier, 15% acrylic
polymer (Carboset.RTM. 525 or Avalure.RTM. AC 315) as film former, and 43%
ethyl alcohol and 40% ethyl acetate as volatile solvents. The typical
topical formulation containing the acidified lacquer composition comprises
1% clotrimazole as active agent, 0.1% concentrated HCl (37% HCl by weight)
as acidifier, 15% acrylic polymer (Carboset.RTM. 525 or Avalure.RTM. AC
315) as film former, 0.7% isopropyl myristate as non-volatile drug
solubilizer, 0.1% butylated hydroxyltoluene as antioxidant, 0.1% citric
acid, and 43% ethyl alcohol and 40% ethyl acetate as volatile solvents.
A typical formulation containing the acidifed lacquer composition which may
be used to treat onychomycosis, comprises from about 0.5 to about 3% of an
antifungal drug as an active agent, from about 0.1% to about 1%
concentrated HCl (37% HCl by weight) as an acidifier, about 15% acrylic
polymer (Carboset.RTM. 525 or Avalure.RTM. AC 315) as a polymeric film
former, 1% isopropyl myristate as non-volatile solvent, 0.1% butylated
hydroxyltoluene as antioxidant, 0.1% citric acid, and 37% ethyl alcohol
and 42.3%-42.7% ethyl acetate as volatile solvents.
A typical formulation containing the acidifed lacquer composition which may
be used to treat vesicolor, psoriasis, ringworm, plantar tinea pedis, Jock
itch, and athlete's foot comprises from about 0.5 to about 3% an
antifungal drug as an active agent, from about 0.1% to about 1%
concentrated HCl (37% HCl by weight) as an acidifier, 3% acrylic polymer
(Carboset.RTM. 525 or Avalure.RTM. AC 315) as a polymeric film former, 1%
isopropyl myristate as non-volatile solvent, 0.1% butylated
hydroxyltoluene as antioxidant, 0.1% citric acid, and 67% ethyl alcohol
and 24.3%-24.7% ethyl acetate as volatile solvents. The anti fungal drugs
in the above examples can be selected from at least one of the following:
clotrimazole, miconazole, terbinafine, amorolfine, ciclopirox olamine,
tolnaftate, fluconazole, econazole, ketocoanzole, itraconazole,
butenafine, and their pharmaceutically acceptable salts.
The invention includes a method of treating disease infected human nails or
disease infected human skin by topically applying 1) an acidified
composition comprising at least one acidifier, at least one volatile
solvent, and at least one active agent; or 2) an acidified lacquer
composition comprising at least one acidifier, at least one volatile
solvent, at least one active agent, and at least one polymeric film former
The terms, acidifier, volatile solvent, active agent, lacquer and polymeric
film former were defined above.
The term "nail" means the horny cutaneous plate on the dorsal surface of
the distal end of a finger or toe. FIG. 1 is a schematic diagram showing
the basic anatomic structure of human nail and its surrounding tissues.
The treatment contemplated by this invention is intended to deliver an
active agent to the nail plate (the stratum corneum unguis) and to the
nail bed (the modified area of epidermis beneath the nail, over which the
nail plate slides as it grows) through the nail plate. Desirably, the
active agent is also concurrently administered to the nail matrix (the
proximal portion of the nail bed from which growth chiefly proceeds) and
nail bed through the skin of the eponychium (commonly called the cuticle)
and the hyponychium (the thickened epidermis underneath the free distal
end of the nail).
The term "applying" refers to any method of physically transferring the
acidified composition to the nail and the skin. Such methods include but
are not limited to painting the composition or lacquer on the surface of
the nail; spraying the composition or lacquer using a spray pump, and
combining the composition or lacquer with a propellant so that it sprayed
on the skin as an aerosol. The term "aerosol" refers to systems consisting
of "pressurized packages" with either compressed gases or liquefied gases
as propellants. Examples of compressed gases are compressed nitrogen and
air. Examples of liquefied gas propellants are propane, isobutane,
n-butane, dimethyl ether, and mixtures thereof. The preferred propellants
are dimethyl ether, and mixture of dimethyl ether and one or more
hydrocarbon propellants. The preferred weight ratio of dimethyl ether to
the hydrocarbon propellant(s) ranges from greater than or equal to about
3:2 (.gtoreq.3.2) respectively.
Typically for the treatment of nail diseases, the composition or lacquer is
initially applied for once or twice per day and may be reduced to once or
twice a week depending upon the intensity and resilience of the underlying
infection.
As used herein the term "disease" refers to fungal diseases, bacterial
diseases and psoriasis.
The fungal diseases of the human nail that can be treated in accordance
with the invention include but are not limited to "onychomycosis." This
disease is typically caused by an infection of Epidermophyton floccosum,
several species of Trichophyton, such as T. rubrum and T. mentagrophytes,
or yeast, such as Candida albicans, or molds. Fungal diseases of the human
skin that can be treated in accordance with the invention include but are
not limited to the diseased portions of the skin surrounding a nail
especially to the eponychium, i.e., the skin tissue above the nail matrix.
This application allows antifungal drug and nail growth promoters to be
absorbed into the eponychium and subsequently into the nail matrix. This
is particularly beneficial, for when the nail growth is accelerated, some
antifungal drug is incorporated into the growing healthy nail to prevent
re-infection by fungi. In addition to onychomycosis, fungal skin diseases
such as versicolor, ringworm, psoriasis, athlete's foot, plantar tinea
pedis, and Jock itch may be treated using the methods and compositions of
this invention. Typically these skin diseases are caused by funguses such
as Trichophyton rubrum, T. mentagrophytes, and Epidermophyton floccosum.
Typically the treatment regimen for skin fungal infections using the
acidified composition or acidified lacquer can be once or twice per day,
preferably once per day, with a duration from less than a week to four
weeks, preferably equal or less than two weeks.
The topical treatment of the invention may be employed in combination with
systemic treatment. For example, an antifungal drug, such as,
itraconazole, terbinafine, griseofulvin or other antifungal drugs, can be
given orally over a period of time. This time period may be concurrently
during the entire topical treatment regimen, or concurrently during a
portion (usually the latter phase) of the topical treatment regimen, or
following the topical treatment.
The invention includes a method of treating healthy human nails or skin by
topically applying 1) an acidified composition comprising at least one
acidifier, at least one volatile solvent, and at least one active agent;
or 2) an acidified lacquer composition comprising at least one acidifier,
at least one volatile solvent, at least one active agent, and at least one
polymeric film former
Since the acidified composition and the acidified lacquer of the invention
are non-irritating they may be used prophylactically to prevent infection.
When used in this manner the acidified lacquer and acidified composition
may be applied once or twice per month. Typically the prophylactic
treatment regimen for fungal infections of the nail and skin using the
acidified composition or acidified lacquer can vary from once or twice per
week to once or twice per month, with the interval between treatments
shorter for the skin and longer for the nail.
In order to illustrate the invention, the following examples are included.
These examples do not limit the invention. They are meant to suggest a
method of practicing the invention. Those knowledgeable in the treatment
of human nails and skin may find other methods of practicing the
invention. However, those methods are deemed to be within the scope of
this invention.
EXAMPLES
As demonstrated in the following examples, various experiments were
conducted in an effort to meet the requirement of a good topical
therapeutic product: (1) enhanced drug delivery; (2) non-irritating to
human issues involved; (3) good drug stability; and (4) convenient to use.
It has been demonstrated that antifungal drug uptake into human nails could
be significantly increased by using the disclosed acidified lacquer
compositions (Example 3, Table 4). In addition it has been demonstrated
that even a greater drug uptake is found when the nails were pretreated
with penetration enhancers (Example 5, Table 6), followed by use of the
acidified lacquer compositions. It has also been demonstrated that skin
substantivity of an antifungal drug against washing, as well as drug
penetration into the skin, was drastically enhanced when the disclosed
acidified lacquer composition was used in comparison to commercial
products (Example 9, FIGS. 6 & 7).
Example 1
Acidification to Enhance Drug Uptake into Human Nail
To evaluate the effect of concentrated acids on miconazole nitrate
solubility, 0.5% or 1.0% of the following acids was added into a liquid
containing 2% miconazole nitrate and ethyl alcohol made up to 100%. The
percentages are all by weight throughout the text. The tests were
conducted at 22.degree. C. under mixing.
As shown in Table 1, among many acids tested for the nail lacquer
acidification, including concentrated hydrochloric acid, sulfuric acid,
phosphoric acid, nitric acid, acetic acid, lactic acid, and glycolic acid,
only concentrated HCl, and concentrated sulfuric acid to a less extent,
could completely solubilize miconazole nitrate in ethyl alcohol. As used
herein, complete solubilization means that the resulting mixture produces
a clear solution. Furthermore, as can be seen in Table 1, this complete
solubilization phenomenon only occurred with the concentrated hydrochloric
acid, and to a less extent, with the concentrated sulfuric acid, but not
with other acids tested.
TABLE 1
Miconazole Nitrate Solubility
Concentrated Acid* 0.5% acid added 1.0% acid added
Hydrochloric acid Clear solution Clear solution
Sulfuric acid Turbid suspension** Turbid suspension**
o-phosphoric acid Turbid suspension Turbid suspension
Nitric acid Turbid suspension Turbid suspension
Acetic acid Turbid suspension Turbid suspension
L(+)-lactic acid Turbid suspension Turbid suspension
Glycolic Acid Turbid suspension Turbid suspension
.cndot.Sources, grades, and pH measurements (with a glass electrode after 1
min) of the concentrated acids.
acidifier pH reading
Hydrochloric acid 37% not available
USP/NF, Spectrum Chemical Mfg. Corp.
Sulfuric acid, 95-98%, USP/NF not available
Spectrum Chemical Mfg. Corp.
o-phosphoric acid, 85% not available
Certified ACS, Fisher Scientific.
Nitric acid, 70.4% not available
Reagent grade, Mallinckrdt.
Acetic acid, 99.8% -0.19 to -0.28
Glacial, J. t. Baker Chemical.
L(+)-lactic acid, 90% 0.31
Fluka
Glycolic Acid, 70% 0.43
Dupont
Salicylic acid, powder 2.92
Spectrum Chem.
0.1N HCl 1.11
1.0N HCl 0.21
10% HCl (w.v) -0.18
**Turning into a clear solution when warming to 32.degree. C.
Example 2
Drug Uptake into Human Nail Clippings from Acidified Solutions
To evaluate the effect of concentrated acids on miconazole nitrate uptake
into human nail, an experiment was conducted as follows. One part of the
acidifier (listed in Table 2) was added into a glass vial containing a
liquid comprised of 2 parts of miconazole nitrate and 97 parts of ethyl
alcohol (denatured, 200 proof). A known weight of human nail clippings was
placed into the vial, which was then tightly capped. The nail partitioning
experiment was conducted at 32.degree. C. for 24 hours under mixing. At
the end of the experiment, the nail clippings were thoroughly washed with
alcohol to remove surface-bound drug. The miconazole nitrate content of
the nail clippings was analyzed by High Pressure Liquid Chromatography
(HPLC), and the results were tabulated in Table 2. It can be seen that the
nail uptake of miconazole nitrate from the acidified solutions was
enhanced by approximately 9 fold using 1% of hydrochloric acid or sulfuric
acid; and 2-3 fold using the other acids tested.
TABLE 2
Miconazole nitrate uptake Enhancement ratio
Concentrated Acid into nail clippings Nail Conc..sub.with acid /Nail
(1%, w/w) (mg drug/g nail) Conc..sub.without acid
Hydrochloric acid 1.39 9.27
Sulfuric acid 1.33 8.87
o-phosphoric acid 0.40 2.67
Nitric acid 0.48 3.20
Acetic acid 0.36 2.40
L(+)-lactic acid 0.48 3.20
Glycolic Acid 0.48 3.20
Salicylic acid 0.33 2.20
Control: no acid 0.15 --
added
Example 3
Drug Uptake into Human Nail Clippings from Acidified Lacquer Formulations
Drug partitioning studies were conducted to evaluate nail uptake of a drug
by immersing human nail clippings in several lacquer formulations for 48
hours at 32.degree. C. under constant stirring. At the end of the
experiment, the drug content in the nail clippings was analyzed by HPLC
after washing off the surface-bound drug. The nail lacquer formulations
used in the drug partitioning studies are shown in the Table 3. The
lacquer formulations contained either miconazole nitrate or itraconazole,
with and without concentrate hydrochloric acid. The results of the drug
partitioning into the nail shown in Table 4, FIG. 2 (miconazole nitrate)
and FIG. 3 (itraconazole). The number on the bars in the figures are the
enhancement ratio, which equals the nail drug content treated with a
HCl-containing lacquer, divided by the nail drug content treated with a
no-HCl-added-lacquer of the same drug concentration. As can be seen, an
increase of 12-33 fold in drug uptake into nail was achieved with the
miconazole nitrate lacquers; and a 38-57 fold increase with the
itraconazole lacquers. These results clearly show that the acidified nail
lacquer compositions significantly enhanced the penetration of antifungal
drug miconazole nitrate and itraconazole into the nail.
TABLE 3
The compositions of lacquer formulations containing either miconazole
nitrate or itraconazole used in the nail uptake experiments and Primary
Dermal Irritation Test (in weight %)
Formulation Conc. CBST
No. Mic. N Itra HCl IPM Eth. Ac EtOH 525
3-1 2.0 0 0.5 1.0 40.0 41.5 15.0
3-2 5.0 0 2.0 1.0 40.0 37.0 15.0
3-3 10.0 0 5.0 1.0 40.0 29 15.0
3-4 2.0 0 0 1.0 40.0 42.0 15.0
3-5 5.0 0 0 1.0 40.0 39.0 15.0
3-6 10.0 0 0 1.0 40.0 34.0 15.0
3-7 0 1.0 0.5 1.0 0 82.5 15.0
3-8 0 2.0 1.0 1.0 0 81.0 15.0
3-9 0 5.0 2.0 1.0 0 77.0 15.0
3-10 0 1.0 0 1.0 0 83.0 15.0
3-11 0 2.0 0 1.0 0 82.0 15.0
3-12 0 5.0 0 1.0 0 79.0 15.0
Mic. N Miconazole Nitrate
Itra Itraconazole
Conc. HCl Concentrate Hydrochloric Acid, 37%
IPM Isopropyl Myristate
EtOH Ethyl alcohol, 200 proof, denatured
CBST525 Carboset .RTM. 525, Acrylic copolymer, B F Goodrich
Eth. Ac Ethyl Acetate
Acidified lacquer formulations demonstrated enhanced drug uptake into human
nail clippings. The nail uptake (nail partitioning) experiments were
conduction in triplicates (n=3). The drug concentrations in the nail were
the average value (AVG) with corresponding standard deviation (STD). The
enhancement ratio of nail uptake of a drug was calculated by dividing the
nail drug content treated with the acidified lacquer formulation of a
particular drug concentration, over the nail drug content treated with a
non-acidified lacquer containing the same drug concentration.
TABLE 4
Drug Content Enhancement
Drug in nail ratio of nail
Formu- Conc. in A = acidified (mg drug/ uptake:
lation lacquer N = Non- gm nail) Content.sub.A /
No. formulation acidified AVG .+-. STD Content.sub.N
3-1 1% Mic. N. A 1.888 .+-. 0.235 12.3
3-2 5% Mic. N. A 2.996 .+-. 0.314 19.1
3-3 10% Mic. N. A 5.255 .+-. 0.465 32.7
3-4 1% Mic. N. N 0.179 .+-. 0.033 --
3-5 5% Mic. N. N 0.157 .+-. 0.037 --
3-6 10% Mic. N. N 0.161 .+-. 0.016 --
3-7 1% Itra A 0.8212 .+-. 0.1253 37.8
3-8 2% Itra A 1.5089 .+-. 0.1263 54.3
3-9 5% Itra A 4.5497 .+-. 0.9011 57.3
3-10 1% Itra N 0.0217 .+-. 0.0107 --
3-11 2% Itra N 0.0278 .+-. 0.0159 --
3-12 5% Itra N 0.0794 .+-. 0.0314 --
Example 4
Skin Irritation Test
Despite the extremely strong acidity of the lacquer formulations, to our
surprise, the nail varnish formulations are not irritating to the skin. A
standard test for skin irritation, called "the Modified Draize Rabbit
Primary Dermal Irritation Test" (PDI), was used to evaluate the acidified
nail lacquers. The test procedures are described briefly as follows. The
test skin sites of the New Zealand White albino rabbits were clipped free
of fur. Skin abrasion was made at each test skin site using the barbed tip
of a sterile 20 gauge hypodermic needle in a "tic-tac-toe" pattern. The
nail lacquer was applied to the prepared test skin site. Observation was
made by a skilled scientist in twenty four hours, and again in seventy two
hours, for any signs of skin irritation, including erythema, eschar, and
edema formation. A score system was used to grade the observed skin
irritation: ranging from the lowest score, 0 (non-rirritant) to the
highest score 8 (severe irritant). The acidified lacquer formulations
tested for PDI include Nos. 3-2, 3-3 and 3-9 (Table 3). All the acidified
lacquers obtained the PDI score "mild". Another skin irritation test,
called "Cumulative Skin Irritation Test" (CSI), was also conducted using
the New Zealand White albino rabbits. The acidified nail lacquers were
applied to the intact skin previously clipped free of fur (i.e., without
previous skin abrasion) twice a week for two and one-half weeks. Prior to
each lacquer application, the dried nail lacquer was first removed from
the test skin using an alcohol swab containing 70% isopropyl alcohol.
Again, all the test results were mild (Table 5). The irritation potential
of the acidified lacquer formulation was also evaluated on human
volunteers. The nail lacquer was applied to the ventral forearm skin of
three volunteers for twenty-four hours. There was no sign of any skin
irritation. In one volunteer, once-a-day application of the lacquer was
continued for two weeks. Prior to each lacquer application, the dried nail
lacquer was first removed from the test skin using an alcohol swab
containing 70% isopropyl alcohol. Again, no sign of skin irritation was
observed.
It should be noted that the acidity of the nail lacquers was extremely
high. Because of the anhydrous nature of the nail lacquers, any direct pH
measurement did not have its normal meaning. However, to put the matter in
perspective, consider the fact that the pH value of 0.1 N HCl is pH 1.0,
whereas the content of the HCl in the nail lacquers tested in this study
were up to five times higher than 0.1 N HCl. That a topical formulation
containing such a high content of a strong acid is still mild to the skin,
is truly surprising and completely unexpected.
TABLE 5
The compositions of lacquer formulations containing either miconazole
nitrate or itraconazole used in the Cumulative Skin Irritation Test
(in weight %), and the test results
Formula Conc.
CBST
No. Mic. N Itra HCl IPM Ascor. P Eth. Ac EtOH
525 CSI
4-1 5.0 0 2.5 1.0 0.1 40.0 36.4
15.0 Mild
4-2 0 5.0 2.5 1.0 0.1 0 76.4
15.0 Mild
4-3 2.0 0 1.0 1.0 0.1 40.0 55.4
0.5 Mild
4-4 0 0 2.5 1.0 0.1 40.0 41.4
15.0 Mild
Mic. N Miconazole Nitrate
Itra Itraconazole
Conc. HCl Concentrate Hydrochloric Acid, 37%
IPM Isopropyl Myristate
Ascor. P Ascorbyl Palmitate
Eth. Ac Ethyl Acetate
EtOH Ethyl alcohol, 200 proof, denatured
CBST Carboset .RTM. 525, Acrylic copolymer
Example 5
Drug Uptake into Nail Clippings Which have been Pretreated with Penetration
Enhancers
Nail penetration enhancers such as N-acetyl cysteine (NAC) have been shown
to promote drug penetration through human nail when a drug formulation
contained the penetration enhancer and the drug (see U.S. Pat. No.
5,696,164). The invention describes a new enhancement method using NAC for
topical drug delivery to the nail.
The essence of the new enhancing method is a nail pretreatment of nail
penetration enhancer(s) prior to the application of an
active-agent-containing formulation. The active agent may be of
therapeutic or cosmetic value. Optionally, the pretreatment formulation
containing enhancer(s) is also comprised of active-agents for therapeutic
and cosmetic purposes. To demonstrate this methodology, experiments were
conducted as follows. Human nail clippings of known weight were immersed
in a pretreatment formulation containing NAC, urea and distilled water of
certain concentrations at 32.degree. C. under mixing for a period of time
(e.g., 24 hours). At the end of the pretreatment procedure, the extent of
nail swelling was determined by weighing the nail clippings after being
blot-dried with paper towel. A drug uptake experiment was then carried out
by immersion of the pretreated nail clippings in the acidified antifungal
lacquer formulations at 32.degree. C. under constant mixing for 48 hours.
The basic composition of the acidified itraconazole lacquer formulations,
and the nail uptake of drug procedures (i.e., nail partitioning) were the
same as described in the previous sections. Table 6 tabulates the results
of nail swelling after the pretreatment, and itraconazole uptake into the
pretreated nail clippings. In general, the drug uptake increased as a
result of pretreatment with nail penetration enhancers. The rank order of
the enhancement with different pretreatment conditions are the following:
urea alone<NAC alone<NAC plus urea. Pretreatment with urea alone showed
rather limited enhancing effect on the drug uptake, whereas NAC alone was
more effective. A combination of NAC and urea, on the other hand, showed a
definite synergistic effect in the enhancement of drug uptake. For
example, pretreatment with 20% urea alone resulted in 4.7 mg drug per gram
nail; pretreatment with 10% NAC alone resulted in 15.45 mg drug per gram
nail. In a sharp contrast, pretreatment with 10% NAC and 20% urea resulted
in 28.46 mg drug per gram nail. The synergistic enhancement of two
enhancers for drug uptake into the nail has an important and practical
implication: it enable the use of a minimal amount of an enhancer which
may be irritating to the skin at high concentration, such as NAC.
It should be noted that, in Table 6, the enhancement ratio of drug uptake
into the nail is meant to compare the effect of pretreatment only. The
acidified drug-containing lacquers were used in all the experiments, and
the non-pretreated nail uptake data was used as the bench mark. On the
other hand, a comparison can also be made between a non-acidified lacquer
of certain drug concentration in a non-pretreated nail uptake experiment
(as shown in Table 4) and an acidified lacquer of the same drug
concentration in a pretreated experiment (as shown in Table 6). Thus
another set of enhancement ratio data can be calculated: for itraconazole
lacquer of 1%, there is a 463-fold increase in drug uptake into nail; for
2% itraconazole lacquer, there is a 826-fold increase; and for 5%
itraconazole lacquer, there is a 759-fold increase, when the nail has been
pretreated with 10% NAC and 10% Urea. This shows that the enhancing power
of the combination (i.e., acidified lacquer and pretreatment) for drug
delivery into nail are remarkable.
TABLE 6
Drug uptake into human nail from acidified itraconazole lacquer after
pretreatment with nail penetration enhancers. All the experiments were
conducted in triplicates (n = 3)
DURING ITRACONAZOLE
PRETREATMENT UPTAKE INTO NAIL
(WT.sub.24 hr /WT.sub.Initial) .times. 100% (mg drug/gm nail)
Nail clippings immersed in Followed by immersion in
pretreatment NAIL acidified lacquer formulations
SWELLING solutions 32.degree. C. for 48 hours
at 32.degree. C. for 24 hours ENHANC.
AVG STD AVG STD RATIO*
NO PRETREATMENT 1% ITRA 0.82 0.12 1
2% ITRA 1.51 0.13 1
5% ITRA 4.55 0.9 1
UREA ALONE
10% UREA 1.31 0.18 2% ITRA 4.71 0.85 3.1
20% UREA 1.49 0.05 2% ITRA 4.7 1.99 3.1
NAC ALONE
10% NAC 1.91 0.08 2% ITRA 15.45 2.19 10.2
20% NAC 2.73 0.34 2% ITRA 30.86 3.48 20.4
NAC + UREA
1% NAC + 1.63 0.10 2% ITRA 7.21 0.97 4.8
10% UREA
2% NAC + 1.53 0.25 2% ITRA 9.6 0.88 6.4
10% UREA
5% NAC + 2.04 0.02 2% ITRA 13.87 0.94 9.2
10% UREA
1% NAC + 1.76 0.12 2% ITRA 8.63 1.32 5.7
20% UREA
2% NAC + 1.60 0.20 2% ITRA 10.6 3.32 7.0
20% UREA
5% NAC + 2.55 0.11 2% ITRA 19.02 1.25 12.6
20% UREA
10% NAC 1.91 0.08 2% ITRA 15.45 2.19 10.2
10% NAC + 2.66 0.10 2% ITRA 24.83 1.67 16.4
10% UREA
10% NAC + 3.52 0.21 2% ITRA 28.46 4.37 18.8
20% UREA
20% NAC 2.73 0.34 2% ITRA 30.86 3.48 20.4
20% NAC + 3.12 0.33 2% ITRA 29.27 3.1 19.4
5% UREA
20% NAC + 3.69 0.13 2% ITRA 37.09 1.68 24.6
10% UREA
20% NAC + 3.94 0.24 2% ITRA 29.04 0.92 19.2
20% UREA
ITRA CONC
10% NAC + 2.50 0.10 1% ITRA 10.05 0.67 12.3
10% UREA
10% NAC + 2.50 0.10 2% ITRA 22.97 1.74 15.2
10% UREA
10% NAC + 2.50 0.10 5% ITRA 60.24 5.99 13.2
10% UREA
*Enhancement ratio is defined as: the drug content in the pretreated nail
divided by the drug content in the non-pretreated nail after immersion in
a nail lacquer of the same drug concentration.
Example 6
Drug Permeation into and through Human Nail Plate
Experiments were conducted to evaluate the drug penetration through human
nails. The experimental procedures are briefly described as follows: (1)
human nail plates were mounted in modified Franz diffusion cells. (2) A
nail enhancer formulation containing 10% NAC and 20% urea was placed in
the donor cells to pretreat the nail plate for 24 hours. (3) After the
pretreatment formulations were removed from the donor cells, lacquer
formulations containing 2% or 5% miconazole nitrate were applied to the
nail plate in the donor cells. At the end of one week from the starting of
the nail pretreatment, the nail lacquers were removed with ethanol swabs.
Steps (2) & (3) were repeated for three more weeks. The experiment was
conducted in triplicate for a total length of four weeks at 32.degree. C.
(AVG.+-.STD, n=3). The effect of occlusive versus non-occlusive conditions
was tested by covering selected donor cells with an occlusive polymer film
after allowing the lacquer sufficient time to dry up. The occlusion test
was used to mimic the condition often caused by the "over-coat" layers of
another nail lacquer. The amount of drug permeated through the nail plate
was determined by analyzing the receptor fluid with HPLC. The drug
concentration in the nail plate was determined.
The nail permeation results were tabulated in Table 7 and plotted in FIG.
4. The permeation profiles in FIG. 4 shows that miconazole nitrate from
the nail lacquers permeated through the nail plate rather rapidly,
especially for those nail plates which had been pretreated with nail
penetration enhancers (i.e., comparing #1-4 with #5). As can be seen from
FIG. 5 and Table 7, the acidified nail lacquers delivered miconazole
nitrate into and through the nail plates even without the help of nail
penetration enhancers. Pretreatment with NAC and urea significantly
increased the drug permeation through the nail. The lacquer containing a
higher drug concentration delivered more drug through the nail. Occlusive
condition further enhanced the drug permeation from the drug-containing
lacquer. Occlusive conditions can be achieved easily by multiple coats of
the drug-containing lacquer, or by "overcoats" of another lacquer, or by
application of an occlusive cover, such as an adhesive-coated polymeric
bandage of predetermined properties, such as certain range of moisture and
gas permeabilities.
TABLE 7
Drug Penetration into and through human nail plate
Drug Total
Permeated Drug in Amount Nail
Permeation into receptor NAIL Delivered Thick-
Conditions (cum .mu.g/cm.sup.2) (.mu.g/cm.sup.2) (.mu.g/cm.sup.2)
ness
Enhancer: Unoccluded 596.2 .+-. 642.10 0.0567
10% NAC & 20% urea 45.92 .+-. 17.32 82.3 cm.
2% Mic. Nit. lacquer* (8856.4
.mu.g/cm.sup.3)
Enhancer: Occluded 814.0 .+-. 866.99 0.0596
10% NAC & 20% urea 52.95 .+-. 7.54 118.2 cm
2% Mic. Nit. lacquer* (12269
.mu.g/cm.sup.3)
Enhancer: Unoccluded 1004.2 .+-. 1074.13 0.0542
10% NAC & 20% urea 69.92 .+-. 60.05 100.9 cm
5% Mic. Nit. lacquer (17365
(4-1) .mu.g/cm.sup.3)
Enhancer: Occluded 1264.8 .+-. 1437.7 0.0559
10% NAC & 20% urea 172.94 .+-. 71.74 520.6 cm
5% Mic. Nit. lacquer (18586
(4-1) .mu.g/cm.sup.3)
No enhancer: Occluded 242.1 .+-. 248.11 0.0339
5% Mic. Nit. lacquer 6.04 .+-. 5.59 98.9 cm
(4-1) (6007
.mu.g/cm.sup.3)
*Similar composition to 4-1, but with a lower drug concentration.
Example 7
Skin Permeation Experiment
To evaluate whether the drug-containing lacquer formulation can be used to
deliver drug into the skin, a skin permeation study was conducted by
applying a lacquer formulation containing 2% miconazole nitrate to a
solvent evaporated in a short period of time, and left a uniform polymer
film on the skin. Table 8 tabulates the compositions of the nail lacquer
formulations tested. A commercial cream product containing 2% miconazole
nitrate (Micatin Cream) was also tested for comparison purpose. The amount
of miconazole nitrate penetrated through the skin and reached the receptor
was analyzed by HPLC. The skin content of the drug, i.e., that retained in
the dermis, was also determined by HPLC. Results in Table 9 and FIG. 5
show that miconazole nitrate was indeed able to diffuse out of the lacquer
layer and to penetrate through the human skin. All the miconazole
nitrate-containing lacquers delivered more drug into the skin. A
comparison of Formulation Nos. 7-3 with 7-4 show that a higher HCl content
in the lacquer led to a higher skin permeation of the drug, indicating the
acid acted like a penetration enhancer in this situation.
Depending on the polymer content, the acidified formulations can be
formulated as lacquer or spray and aerosol. A lacquer formulation contains
relative high polymer content, and forms a polymer film upon application.
On the other hand, a low-polymer-content formulation can be sprayed by a
pump operated manually, or powered by compressed or liquefied gases, i.e.,
in the forms of liquid spray or aerosol. In fact, one of the formulations
(i.e., No. 4-3) in Table 5 tested for skin irritation was formulated
specifically as liquid spray. It contained only 0.5% Carboset.RTM. 525 as
polymer film former, instead of 15% polymer in the other lacquers. After
being applied to skin with a spray pump, this formulation formed an almost
invisible, discrete layer on the test skin site.
TABLE 8
The compositions of lacquer formulations containing
miconazole nitrate used in the skin permeation study (in weight %)
Formula No. Mic. N. Conc. HCl IPM EtOH CBST 525
7-1 2 1 0 87.0 10
7-2 2 2 0 86.0 10
7-3 2 1 0.5 86.5 10
7-4 2 2 0.5 85.5 10
Control (Bench mark): Micatin Cream containing 2% miconazole nitrate in a
cream base.
TABLE 8
The compositions of lacquer formulations containing
miconazole nitrate used in the skin permeation study (in weight %)
Formula No. Mic. N. Conc. HCl IPM EtOH CBST 525
7-1 2 1 0 87.0 10
7-2 2 2 0 86.0 10
7-3 2 1 0.5 86.5 10
7-4 2 2 0.5 85.5 10
Control (Bench mark): Micatin Cream containing 2% miconazole nitrate in a
cream base.
Example 8
Drug Stability in Acidified Lacquer
To evaluate the drug stability in the acidified lacquer formulations,
accelerated drug stability tests were conducted at elevated temperatures
over certain periods of time (a method widely applied in pharmaceutical
industry). The stability results for the formulations tested (e.g.,
Formulations 4-1, 4-3, 3-8, and 3-9) indicate that the drug formulations
are stable in the acidified lacquers, and would satisfy the required
two-year shelf life. This is a surprise since it is well known that the
presence of a strong acid usually cause drug decomposition through
acid-induced degradation reactions.
Example 9
Increased Skin Substantivity of Miconazole Nitrate by the Present Invention
The purpose of this experiment was to examine the skin substantivity of the
antifungal drug miconazole nitrate from a liquid spray formulation as an
example of the present invention. This liquid spray (hereto, the Spray
Formulation) was compared to two commercial products for athlete's foot
treatment, which contained the same drug and concentration as the Spray
Formulation. In the U.S., topical antifungal products containing 2%
miconazole nitrate for athlete's foot treatment require a regimen of
twice-a-day application and duration of four weeks. If skin substantivity
of miconazole nitrate can be improved (i.e., drug retention on the skin is
increased), a more patient-friendly product can be made with a far less
frequent dosing regimen and a much shorter therapy duration.
In vitro skin permeation tests combined with a washing procedure were
conducted using dermatomed human cadaver skin mounted on Franz diffusion
cells (n=6). The three formulations tested were the Spray Formulation,
Micatin.RTM. cream (hereinafter Formula A) and Lotrimin.RTM. spray liquid
aerosol (hereinafter Formula B). Table 10 shows all the compositions of
the preparations tested.
TABLE 10
Compositions of the preparations tested
Formula A:
Miconazole nitrate (2%) -- active ingredient
Benzoic acid
BHA
Mineral Oil
Peglicol 5 Oleate
Pegoxol 7 Stearate
Purified water
Formula B:
Miconazole Nitrate (to deliver 2%) -- active
ingredient
Alcohol SD-40 (17% w/w)
Cocamide DEA
Isobutane
Propylene glycol
Tocopherol (Vitamin E)
The Spray Formulation
Ingredient % (w/w)
Miconazole Nitrate, USP 2.00
Isopropyl Myristate, USP 1.00
Ethyl Alcohol (40B), USP 70.00
Avalure Polymer 3.00
Menthol, USP 1.00
Ethyl Acetate, USP 22.00
Conc. HCl, USP 1.00
To begin the experiment, a test formulation was applied to the skin surface
to form a thin layer. At 0.5, 12, or 24 hours, a washing procedure was
conducted to mimic normal shower/bath by washing the skin surface with 5
milliliters of warm water (32.degree. C.). At the end of the 24-hour
permeation test, miconazole nitrate retained on the skin surface was
removed with methanol swabs, and the epidermis was separated from dermis.
The drug content in wash liquids, methanol swabs, epidermis, dermis, and
receptor media was analyzed by HPLC.
As shown in FIG. 6, approximately 62-81% of miconazole nitrate was found to
be retained on the skin surface after washing. In sharp contrast, the
surface-retained drug for Formula A cream was less than 9%, and for
Formula B aerosol was less than 0.6%. The rank order of miconazole nitrate
in the Spray Formulation treated samples is the following:
surface-retained (methanol swabs)>>wash liquids>epidermis>dermis>receptor
fluid. On the other hand, the rank order for Formula A cream and Formula B
is: wash liquids>>surface-retained>epidermis>dermis>receptor fluid. The
different exposure times before washing did not have any marked effect on
the substantivity results. The data confirms that the Spray Formulation
indeed provides superior drug substantivity to the skin, as opposed to the
commercial cream and aerosol formulations. The significantly enhanced drug
retention on the skin surface by the Spray Formulation should allow a less
frequent dosing regimen than the current products, and thus improve
patient compliance.
FIG. 7 shows the relative miconazole content in epidermis, dermis and
receptor media. As can be seen from the figure, miconazole concentrations
in the epidermis and dermis from the Spray Formulation were several fold
higher than those from the Formula A cream and Formula B aerosol. Drug
content in the receptor fluid was very low. Epidermis is the target tissue
for athlete's foot treatment. A higher antifungal drug concentration in
epidermis would assure complete elimination of the pathogenic
dermatophytes, which should enable a reduction in dosing frequency (e.g.,
from twice a day to once a day) and treatment duration (e.g., from four
weeks to one or two weeks). There is a general trend of increasing drug
penetration into the skin with prolonged skin exposure time before washing
with the Formula A cream and Formula B aerosol. Interestingly, for the
Spray Formulation, miconazole nitrate penetration into the skin was
reduced as the exposure time before washing increased. This was probably
because of the drying effect from the volatile solvents in the
substantially anhydrous Spray Formulation. The drug release from the
binding film might have been hindered when the skin surface was very dry.
After the washing process, the residual moisture content might have
facilitated the drug release and, thus increased drug penetration into the
skin. Since the dermatophytes causing the athlete's foot tend to prevail
in a high moisture environment, the unique moisture-triggering drug
release from the Spray Formulation should be beneficial to the athlete's
foot treatment.
Based on the amount of miconazole nitrate washed off or retained on the
skin among the three formulations tested, it can be concluded that the
newly developed miconazole nitrate Spray Formulation provides superior
skin substantivity over the two commercial products tested (i.e., Formula
A cream and Formula B spray liquid aerosol). The significantly enhanced
drug retention on the skin surface by the Spray Formulation should allow a
less frequent dosing regimen than the current products, and thus improve
patient compliance. In addition, several fold more miconazole can be
delivered into the skin by the Spray Formulation as opposed to the
commercial products. Because epidermis is the target tissue for athlete's
foot treatment, a higher antifungal drug concentration in epidermis would
assure complete elimination of the pathogenic dermatophytes. These
findings confirmed that the present invention resulted in a better topical
antifungal product for athlete's foot treatment, which is more
patient-friendly with a reduced dosing frequency and treatment duration,
and likely to be more efficacious than the commercial products presently
available with the same antifungal drug.
Example 10
Aerosolized Acidified Lacquer Composition
The "Spray Formulation" liquid composition in Example 9 (as shown in Table
10) was aerosolized following known procedures using dimethyl ether and a
mixture of dimethyl ether with n-butane. The aerosol compositions and
results are shown in Table 11. The physical appearances of the resultant
aerosols were observed through transparent aerosol packages.
TABLE 11
Aerosolized miconazole nitrate lacquer and the resultant aerosols
Spray
Composition Formulation Propellant(s) Physical appearance of
Number (wt/wt %) (wt/wt %) resultant aerosols
1 35% 65% dimethyl ether Clear liquid, one phase
system
2 35 45% dimethyl ether Clear liquid, one phase
20% n-butane system
3 35 30% dimethyl ether Turbid liquid, two
35% n-butane phase system
The aerosolized lacquer compositions 1 & 2 are preferable aersols with good
content uniformity, where as the composition 3 is less desirable since the
precipitation would likely cause non-uniform deposition of the drug during
application, and would also likely to result in malfunction of the aerosol
spray valve by clogging up the orifice.
Example 11
Drug Partitioning Studies With Various Concentrations of Acidifiers
Drug partitioning studies were conducted to evaluate formulation acidity on
nail uptake of miconazole nitrate from nine nail lacquer formulations. All
the formulations contain the same drug concentration (2% miconazole
nitrate), but different amount of acidity modifiers, namely, concentrated
HCl (37% HCl) 2%, 1.5%, 1%, 0.5% and 0%, or concentrated NaOH solution
(10% NaOH in distilled water) 0.5%, 1%, 1.5%, and 2%. The rest of the
formulations include 1% isopropyl myristate, 40% ethyl acetate, 15%
Carboset.RTM. 525, and ethyl alcohol to 100%. (All the percentages cited
are by weight). The experiments were conducted in triplicate, and
experimental procedures were the same as those described in Example 3. The
resultant nail drug contents are tabulated in the following table. The
enhancement ratio refers to the ratio of a nail drug content from a
lacquer containing an acidity modifier to that from a lacquer containing
no acidity modifier (i.e., Formulation No. 5). It can be seen that both
HCl and NaOH increased drug uptake into the nail. The extent of the
increase in drug uptake is much greater with HCl. The highest drug uptake
occurred with 0.5% concentrated HCl, followed by 1% concentrated HCl.
TABLE 12
Miconazole
Nitr in nail
Conc. HCl Conc. NaOH (mg drug/ Enhance-
Formulation (37%) Added (10%) Added gm nail) ment
Number. (w/w %) (w/w %) AVG STD Ratio
1 2 -- 1.36 0.07 10.5
2 1.5 -- 1.48 0.23 11.5
3 1 -- 1.63 0.37 12.6
4 0.5 -- 1.89 0.24 14.6
5 0 -- 0.13 0.04 1.0
6 -- 0.5 0.16 0.08 1.2
7 -- 1 0.30 0.03 2.3
8 -- 1.5 0.25 0.01 2.0
9 -- 2 0.25 0.03 2.0
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